Human papillomavirus 16 E6 variants differ in their dysregulation of human keratinocyte differentiation and apoptosis

Ingeborg Zehbe*, Christina Richard, Correne A. DeCarlo, Anny Shai, Paul F. Lambert, Hava Lichtig, Massimo Tommasino, Levana Sherman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

L83V-related variants of human papillomavirus (HPV) 16 E6, exemplified by the Asian-American variant Q14H/H78Y/L83V, were shown to be more prevalent than E6 prototype in progressing lesions and cervical cancer. We evaluated functions relevant to carcinogenesis for the E6 variants L83V, R10/L83V and Q14H/H78Y/L83V as well as the prototype in a model of human normal immortalized keratinocytes (NIKS). All E6 expressing NIKS equally abrogated growth arrest and DNA damage responses. Organotypic cultures derived from these keratinocytes demonstrated hyperplasia and aberrantly expressed keratin 5 in the suprabasal compartment. In contrast, differentiation and induction of apoptosis varied. The E6 variant rafts expressed keratin 10 in nearly all suprabasal cells while the prototype raft showed keratin 10 staining in a subset of suprabasal cells only. In addition, E6 variant NIKS expressing R10G/L83V and Q14H/H78Y/L83V were more prone to undergo cell-detachment-induced apoptosis (anoikis) than NIKS expressing E6 prototype. The combined differentiation and apoptosis pattern of high-risk E6 variants, especially of Q14H/H78Y/L83V, may reflect a phenotype beneficial to carcinogenesis and viral life cycle.

Original languageEnglish
Pages (from-to)69-77
Number of pages9
JournalVirology
Volume383
Issue number1
DOIs
StatePublished - 5 Jan 2009

Funding

FundersFunder number
Israel's Ministry of Science, Culture and Sport
Northern Cancer Research Foundation
National Institutes of HealthCA022443
National Cancer InstituteR01CA098428
Deutsche ForschungsgemeinschaftSFB 432-A9
Ministry of Science and Technology1841

    Keywords

    • Apoptosis
    • Differentiation
    • E6 prototype
    • E6 variant
    • Human papillomavirus 16
    • Keratinocyte
    • Proliferation

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